The present invention relates to the use of polyanionic and polyanionically-derivatised natural polysaccharides or non-derivatised natural polysaccharides for inhibiting alkaline phosphatase as well as to oral preparations comprising these compounds.
In the dental area there is often the problem of formation of plaque (tartar, calculus) produced by bacterial adhesion to natural or artificial teeth or to the gum and promoting the development of caries and gum diseases such as periodontosis. Tartar is understood to mean deposits which form at the margin of the gum on the surface of the teeth. These deposits consist both of inorganic materialxe2x80x94in particular calcium hydrogenoxylapatite (HAP)xe2x80x94and of organic components, such as epithelial cells, food particles, saliva sediments and different kinds of microorganisms.
This whitish, yellowish or often blotchy tartar is undesirable not only because of its appearance but mainly because it gives constant occasion to irritations of the oral mucosa and to the development of gingivitis and diseases of the teeth and teeth socket. Such deposits are prevented on the one hand by daily dental care and by the concomitant microdecalcification. In addition, it is usually necessary to have the dentist remove tartar mechanically from time to time.
Safe and effective agents for inhibiting tartar formation are, for example, the water-soluble, molecularly dehydrated polyphosphates known as sequestrants and chelating agents, such as hexametaphosphates, tripolyphosphates and pyrophosphates, which prevent the formation of HAP (cf. U.S. Pat. No. 4,515,722). In oral application, however, the effect of these compounds is significantly reduced by the saliva enzymes present in the mouth and throat area, such phosphate compounds being hydrolysed in particular by alkaline phosphatases.
U.S. Pat. No. 5,094,844 proposes to reduce the deactivating effect of alkaline phosphatase, i.e. the hydrolysis of the linear molecularly dehydrated polyphosphates, by addition of an anionic polyvinyl phosphonate.
It is the object of this invention to provide further agents which reduce the negative effect of alkaline phosphatase.
Surprisingly, it has now been found that the use of polyanionic and polyanionically-derivatised natural polysaccharides or non-derivatised natural polysaccharides has an inhibiting effect on alkaline phosphatase.
Accordingly, this invention relates to the use of polyanionic and polyanionically-derivatised natural polysaccharides or non-derivatised natural polysaccharides for inhibiting alkaline phosphatase.
In particular, this invention relates to the use of polyanionic and polyanionically-derivatised natural polysaccharides for inhibiting alkaline phosphatase.
The polyanionic and polyanionically-derivatised natural polysaccharides used are preferably
mucopolysaccharides and other polyanionic natural polysaccharides, such as hyaluronic acid or carageenan,
polyanionic derivatives, for example sulfates, methylcarboxylates, phosphates etc. of natural, nonanionic polysaccharides, such as dextrans, xanthans, glucans.
Polyanionically-derivatised natural polysaccharides are preferably those compounds which contain phosphate groups, phosphonate groups or methylphosphonate groups, such as
chitin derivatives, for example sulfochitins, carboxymethylchitins, phosphochitins or, in particular,
chitosan derivatives, for example sulfochitosans, carboxymethylchitosans or, very particularly, phosphochitosans.
The polyanionic and polyanionically-derivatised natural polysaccharides used according to this invention preferably have a molecular weight of  greater than 5000.
Preferred phosphochitosans are in particular phosphonomethylated chitosans corresponding to formula 
wherein
R1 is hydrogen or a radical of formula 
xe2x80x83R2 is a radical of formula (1a);
X1 and X2 are each independently of the other hydrogen, C1-C5alkyl or an alkali ion or ammonium ion; and
n is 20 to 4000.
Very particularly preferred are phosphonomethylated chitosans of formula 
wherein
X1 and X2 are as defined for formula (1).
Most interesting are those compounds of formula (1) or (2), wherein
X1 and X2 are each independently of the other alkali metal, and
n is 20 to 1000.
The non-derivatised natural polysaccharides used according to this invention are preferably glucans. It is preferred to use xcex2-1,3-glucans corresponding to formula 
wherein
n is a number corresponding to an average molecular weight (MW) in the range from  greater than 5xc3x97103 to 10xc3x971010 and, very particularly, from 105 to 108.
It has also been found that the polyanionic and polyanionically-derivatised natural polysaccharides and the non-derivatised natural polysaccharides used according to this invention, in particular the phosphonomethylated chitosans of formulae (1) and (2) and the xcex2-glucans of formula (3), inhibit the adhesion of microorganisms, in particular of anaerobic microorganisms, on solid surfaces, especially in holes, interspaces, deposits, pockets in the mouth and throat area, and that they thus reduce or inhibit the negative effects of these germs, in particular the formation of plaque and calculus, or dental decay, bad breath (malodor) and deposits on dentures.
These compounds can also detach the microorganisms from solid surfaces (desorption).
Forming complexes with the Zn, Sn and Mn, Al, Sb, Zr, La, Hf, Ta, Ir, Gd metals, these compounds are furthermore able to desensitise e.g. over-sensitivity on teeth.
The buffer capacity of the phosphonomethylated chitosan stabilises the intrabuccal pH and prevents hyperacidity and hence tooth decay.
In contrast to polyvinyl phosphonates and similar derivatives of synthetic polymers, the phosphonomethylated chitosans of formulae (1) and (2) and the glucans of formula (3) are compounds which are biocompatible and completely bio-degradable.
The preparation of these compounds is carried out by phosphonomethylation of chitosan in a manner known per se. Further details on their preparation may be found in EP-A-0,713,882.
In another of its aspects, this invention relates to an oral composition, which comprises
(a) 0.01 to 10% by weight, preferably 2 to 5% by weight, of at least one linear molecularly dehydrated polyphosphate salt, and
(b) 0.0001 to 5% by weight of a polyanionic and polyanionically-derivatised natural polysaccharide.
The polyphosphate salts (=component (a)) used according to this invention, for example the hexametaphosphate, tripolyphosphate and pyrophosphate salts which are effective as active substance against the formation of bacterial plaque in the novel oral composition, are water-soluble alkali metal salts, such as the sodium, potassium or ammonium salts, and mixtures thereof. These compounds are known as agents preventing bacterial plaque from U.S. Pat. Nos. 4,627,977 and 4,806,340.
Component (a) in the novel oral composition is preferably hexametaphosphate, tripolyphosphate, pyrophosphate or mixtures of these compounds.
The polyphosphates can comprise, for example, 2 to 120 phosphorus atoms and are used in the novel oral composition in amounts from 0.01 to 10% by weight, preferably from 2 to 5% by weight, based on the total weight of the composition.
Pyrophosphate is preferably used as a mixture of tetrapotassium pyrophosphate and tetrasodium pyrophosphate.
The novel composition may also contain antimicrobial active substances, for example phenol derivatives, diphenyl compounds, benzyl alcohols, chlorohexidine, C12-C14alkylbetaine, C8-C18fatty acid amidoalkylbetaine, amphoteric surfactants, trihalocarbanilides, quaternary ammonium salts and, very particularly, 2-hydroxydiphenyl ethers of formula 
wherein
Y is chloro or bromo,
Z is SO2H, NO2 or C1-C4alkyl,
r is 0 to 3,
o is 0 to 3,
p is 0 or 1,
m is 0 or 1, and
n is 0 or 1.
Very particularly preferred compounds are those of formula 
The novel oral composition can also comprise compounds releasing fluoride ions which are effective against caries formation, for example inorganic fluoride salts, such as sodium fluoride, potassium fluoride, ammonium fluoride or calcium fluoride, or organic fluoride salts, for example amine fluorides which are known under the tradename Olafluor. These compounds may be present in the novel composition in amounts of 0.005 to 3% by weight, depending on solubility and kind of composition.
The novel oral composition is preferably liquid, for example in the form of a mouth wash or mouth rinse, the composition preferably being a 1:1 to 20:1, preferably a 2:1 to 10:1, mixture of water and alcohol.
The pH of the novel oral composition is 4.5 to 9, preferably 5.5 to 8.
The novel oral composition can also be in solid or pasty form, for example in the form of tooth powder, tooth tablet, toothpaste, tooth gel or tooth cream. Such a solid or pasty composition usually comprises an orally acceptable, water-insoluble polishing material. Examples of such polishing materials are water-insoluble metaphosphates, tricalcium phosphates, dehydrated dicalcium phosphates, calcium pyrophosphates, aluminium silicates, zirconium silicates, bentonite, or mixtures of these compounds. The polishing material is usually present in the solid or pasty composition in amounts of 10 to 90% by weight, preferably of 10 to 75% by weight.
The novel oral composition can also contain further materials, for example whitening agents, preservatives, silicones, chlorophyll compounds, other agents for the prevention of bacterial plaque, urea, diammonium phosphates, and mixtures thereof. These adjuvants are present in the novel compositions in such concentrations that the positive properties of the composition are not affected.
Additionally, the novel composition may contain flavouring and sweetening agents, for example peppermint oil, eucalyptus, marjoram, cinnamon, saccharin and the like.
The novel oral composition can be incorporated into lozenges, chewing gum or other products, for example by being stirred into a warm gum material or by coating the exterior surfaces of a chewing gum.